Abstract. Despite treatment with effective anti-retroviral therapy, HIV-infected individuals are at in- creased risk for the development of COPD, manifesting as emphysema, with a higher incidence than the general population developing at an earlier age. Based on the knowledge that the first pathologic manifestations of COPD are in the small airway epithelium (SAE), that the lung destruction that char- acterizes emphysema begins in the alveoli surrounding the SAE and preliminary data demonstrating that airway basal stem/progenitor cells (BC) are capable of expressing a variety of destructive prote- ases, subsets of airway BC express HIV receptors, and that HIV can induce BC to up-regulate ex- pression and release of matrix metalloproteinase (MMP) 9 via triggering the HSPG2 receptors and ERK and AKT pathways, we hypothesize that there are subsets of human small airway BC that have receptors for HIV, and consequent to the interaction with HIV, these BC subsets are pathologically reprogrammed to acquire a ?tissue destructive? phenotype that initiates local alveolar destruction. To evaluate this hypothesis, we propose 3 aims. Aim 1. To assess the hy- pothesis that subsets of the population of human small airway BC have receptors for HIV, and that HIV can interact with and reprogram these BC subpopulations. Based on preliminary data, HIV will bind to, but not replicate in BC, using single cell RNA sequencing and FACS sorting, we will identify and characterize the susceptible BC populations and the specific BC HIV receptors. Aim 2. To examine the hypothesis that, consequent to HIV interaction, airway BC subsets are patho- logically reprogrammed to acquire a ?tissue destructive? phenotype, capable of initiating con- nective tissue destruction, and that these processes are exaggerated by cigarette smoke. Us- ing the relevant BC subpopulations, alone or in the presence of cigarette smoke, studies will be car- ried out to characterize the HIV-induced BC ?tissue destructive? phenotype, identify the specific recep- tors and pathways in BC activated by HIV binding, and to demonstrate that inhibition of these path- ways will return the BC ?tissue destructive? phenotype to normal. Aim 3. To investigate the hypoth- esis that airway BC of HIV+ individuals, and to greater extent, HIV+ individuals that smoke, have acquired a ?tissue destructive? phenotype in vivo, and that this process continues after HIV treatment with highly active anti-retroviral therapy. To validate the in vitro studies in aims 1-2, airway BC recovered by bronchoscopy and brushing of the SAE of HIV+ (uncontrolled and controlled) of nonsmokers and smokers will be assessed for the ?tissue destructive? phenotype com- pared to comparable HIV? individuals, and determine whether this phenotype can be reversed with relevant pathway inhibitors.